Epilepsy is a disorder marked by recurring motor, sensory, or psychic malfunctions which may include unconsciousness or convulsive movements. The International League Against Epilepsy Revised Classification of Epileptic Seizures (1981) categorized the spectrum of epileptic seizures from partial to generalized. A form of generalized convulsive seizure is the "grand mal" or generalized "tonic-clonic" seizure. Such seizures usually involve a relatively short, 10-30 second, tonic phase noted by flexion and extension of muscles, but no shaking followed by a longer, 15-60 second, clonic-tonic phase manifesting as rhythmic muscle group shaking. Hereinafter the terms "seizure", "grand mal seizure", "epileptic seizure", and "maximal seizure" are used interchangeably and synonymously with the generalized tonic-clonic seizure as previously outlined herein.
Many drugs are used to treat epilepsy, generally referred to as anticonvulsants. The older and well tested anticonvulsants include phenobarbital and primidone, neither of which are in common use today because of side effects and phenytoin (which goes by the brand name DILANTIN.TM.) and cabamazepine (TEGRETOL.TM.) and valproate (DEPAKOTE.TM., EPILIM.TM.).
Newer anticonvulsants, such as felbamate (FELBATOL.TM.), gabapentin (NEURONTIN.TM.), lamotrigine (LAMICTAL.TM.), tiagabine (GABITRIL.TM.) and topiramate (TOPAMAX.TM.), are technically marketed in the United States as "adjunctive anticonvulsants" because they are used in combination with older anticonvulsants. Such newer anticonvulsants may prove more useful in treating epilepsy than older drugs, but more testing and research will be necessary. The search for more effective anticonvulsant drugs continues.
Research into the effectiveness of new anticonvulsant drugs typically involves screening candidate drugs in small mammals such as mice or rats (hereinafter "test animal") prior to clinical evaluation on humans. In order to gauge the efficacy of a candidate drug, its anticonvulsive effect is observed in a test animal that may have been electrically induced to have a grand mal seizure. An electrical stimulator (hereinafter simply referred to as a "stimulator") is used to generate a sufficient stimulus to induce a grand mal seizure in a test animal. The use of electrically-induced seizures in test animals for studying the effects of anticonvulsant treatments, drug therapy and other procedures dates back at least as early as 1937.
The effects of various levels of electrical stimulation in test animals, particularly rats, is disclosed in Lowell A. Woodbury and Virginia D. Davenport, Design and Use of a New Electroshock Seizure Apparatus, and analysis of Factors Altering Seizure Threshold and Pattern, Arch. Int. Pharmacodyn., Vol. XCII, No. 1, 1952, the entire disclosure of which is herein incorporated by this reference and is hereinafter referred to as Woodbury and Davenport.
A maximal seizure in a test animal, as disclosed in Woodbury and Davenport, may be broken down into distinct phases. The first phase is a hindleg flexor component of the tonic phase, wherein the test animal flexes (contracts or pulls inward) its hindlegs. This first phase lasts approximately four seconds for a rat. The second phase is a hindleg extensor component of the tonic phase, wherein the test animal extends its hindlegs. This second phase lasts for approximately six seconds for a rat. The third phase includes intermittent, whole-body clonus (clonic phase), wherein the test animal's movements include rapidly alternating muscular contraction and relaxation. This third phase lasts for approximately five seconds in a rat. The fourth and final phase is muscular relaxation followed by seizure termination.
Candidate anticonvulsant drugs are typically selected based on their ability to shorten or eliminate any of the first three phases of a grand mal seizure in a test animal. For this reason, it is particularly important to measure the first three phases of the seizure to determine to what extent a given anticonvulsant drug reduces the severity of a seizure.
Woodbury and Davenport disclose a conventional apparatus for generating an stimulus suitable for inducing seizures in test animals. The Woodbury and Davenport stimulator delivers a 60 Hertz sinusoidal electrical stimulus. The Woodbury and Davenport stimulator includes a variable transformer rated at 2000 volts rms (root mean square) and provides five current ranges, 10, 25, 50, 100 and 500 milliamperes. Current ranges are selected by changing series resistance. The current is preset to the desired value by setting the primary voltage using the variable supply transformer and a voltmeter calibrated in terms of the current delivered. The voltmeter is calibrated using a 500 ohm dummy load in series with an ammeter placed across the output terminals. A switch is manually closed and the variable transformer turned up until the current through the dummy load has a given value. A potentiometer is adjusted until the ammeter reads the given value. The ammeter is thus calibrated and may be read directly. The resistance of the test animal is assumed to be 500 ohms.
The Woodbury and Davenport stimulator also discloses a conventional timing circuit including a capacitor charged from a regulated power supply which is discharged through a series resistor using a relay. The length of time the relay is closed may be varied by varying the series resistance.
Noticeably lacking in the Woodbury and Davenport stimulator is any kind of timing mechanism for recording the seizure phases (e.g., hindleg flexor tonic, hindleg extensor tonic, whole-body clonic, etc.) which is critical to evaluating the efficacy of an experimental anticonvulsant drug. The use of solid state components in a stimulator is also preferred because of superior reliability, and is clearly lacking in the vintage Woodbury and Davenport stimulator.
Another apparatus currently used in research laboratories is the Hugo Sachs (Freiburg, Germany), Type 221, stimulator. However, the Hugo Sachs device also does not appear to have timing mechanisms for recording the distinct seizure phases of test animals during anticonvulsant drug screening.
None of the above aforementioned devices and publications appears to disclose an apparatus capable of delivering a stimulus with a wide range of current ranges with built-in timers for recording phases of the induced seizures. It is desirable to have such a stimulator because the efficacy of a candidate anticonvulsant drug is in part measured by its effect on reducing the duration of a given seizure, which, in turn, has distinct phases. Additionally, none of the prior art devices appear to have a foot switch which allows the user to change the operational state of the stimulator and mark timing events while leaving both hands free to secure the electrodes on the test animal and position the animal until the stimulus is delivered. Thus, a need in the art exists for a stimulator and methods for inducing epileptic seizures and measuring the phases of the induced seizures in test animals for screening anticonvulsant drugs.